This program provides for understanding and improving influenza virus vaccines and includes basic studies of the biology of influenza virus replication as well as clinical studies of the immunologic properties of influenza vaccines. Reassortant influenza viruses are produced with A/Puert Rico/8/34 (PR8), an H1N1 strain, as a donor of increased yield and current human influenza A viruses as donors of hemagglutinin (HA) and neuraminidase (NA) desired for vaccines. The genomic composition of the reassortants is compared to the ability to replicate. In one series, less than 10% of 125 single egg progeny H3 reassortants yielded units of HA (HAU) similar to PR8 All ultimately were found to contain the N1 gene for NA from PR8. Although the N1 gene segment was not always identified early, all strains with high HAU converted to N1 (with or without PR8 matrix gene) after several subsequent passages. This indicates that NA contributes to viral vigor, tha low numbers of persisting H3N1 virions have survival advantage over the majority H3N2 virions. The finding is applicable to standardization of selection of reassortants. Immunologic priming in infants is studied to understand the impact of priming on subsequent responses to influenza vaccine. Previous studies indicate that priming by natural infection result in a greater magnitude of antibody response to booster immunization than does priming with current influenza vaccines. As a confirmation, infants under one year of age were randomized to receive priming by live attenuated vaccine (H1N1) and inactivated vaccine (H3N2 and B) or priming by inactivated vaccine (H1N1, H3N2 and B). After reimmunization with inactivated vaccine six months later, geometric mean titers (GMT) and individual titers for hemagglutination inhibition (HI) were clearly higher for H1N1 among the infants who were primed by live vaccine than for the infants who received inactivated vaccine for priming. GMTs by HI for the tw other vaccine components were no different between the two groups of infants. The results support previous findings and suggest that live attenuated vaccine may provide a superior strategy for immunologic priming of infants against influenza viruses.